Progress in Nutrition 2019; Vol. 21, N. 3: 498-506 DOI: 10.23751/pn.v21i3.6771 © Mattioli 1885

Review

L- potential in acrylamide mitigation from foodstuff: a mini-review Naveed Munir1,4, Muhammad Anjum Zia2, Sumaira Sharif3, Imtiaz Mahmood Tahir4, Muhammad Jahangeer1, Irum Javed5, Muhammad Riaz6, Muhammad Usman Sarwar7, Muhammad Akram7, Syed Muhammad Ali Shah7 1Department of Biochemistry, Government College University Faisalabad, Pakistan; 2Department of Biochemistry, University of Agriculture Faisalabad, Pakistan; 3College of Biosystem, Engineering and Science, Zhejiang University, China; 4College of Allied Health Professional, Directorate of Medical Sciences, Government College University Faisalabad, Pakistan; 5Department of Biochemistry, Sardar Bahadur Khan Women University, Quetta, Pakistan; 6Department of Allied Health Sciences, Sargodha Medical College, University of Sargodha, Sargodha, Pakistan; 7Department of Eastern Medicine, Directorate of Medical Sciences, Government College University Faisalabad, Pakistan - E-mail: [email protected]

Summary. L-Asparaginase (E.C. 3.5.1.1, LA) also known as L- amidohydrolase, specifically catalysis the breakdown of amino acid asparagine to aspartic acid and ammonia. It reduces the level of acrylamide that is produced during the of starchy . L-Asparaginase is widely distributed in animals, plants, and microorganisms. In food industries, acrylamide synthesized during the process of baking and at high temperatures under low moisture content during , a non-enzymatic reaction. As acrylamide is a potential , so strategies for its mitigation have significant importance on its level in the final product. Asparagine acts as a precursor in the process of acrylamide synthesis, so utilization of L-Asparaginase reduced its concentration in the final product. In this review, we have discussed the various pathways of acrylamide syn- thesis as well as different strategies for its elimination from final food products.

Key words: L-Asparagine, carcinogen, Maillard reaction, elimination, Food

Introduction microorganisms. So, a large number of industrial pro- cesses in the area of environmental, industrial and food L-Asparaginase (E.C. 3.5.1.1) has been proved to technology make use of enzymes at a range of stages be a predominantly potential therapeutic agent for the (3). L-Asparaginase could be produced from a wide treatment of different types of especially acute range of fungi, yeasts, bacteria, algae and actinomycet- lymphocytic leukemia (ALL) in children (1). In ad- es in ample amount under different cultural conditions dition, L-asparaginase produces aspartate which acts as well as could be isolated from various plants (4). as aprecursor for the production of ornithine in urea L-Asparaginase from bacterial sources consists four cycle as well as acts as aprecursor for the formation identical subunits as tetrameric protein. Each subunit of oxaloacetate to generate through gluconeo- has 35.6 kDa mol. weight determined by x-ray crystal- genic pathway within the human body (2). Moreover, lographically and each subunit have C1377H2208N382O442S17 L-asparaginase applications in food industries for the s mol. formula (5). elimination of acrylamide from starchy food made it Acrylamide (CH2=CH–CONH2; 2-propena- highly demanded agent in food processing. As en- mide), has 71.08 kDa molecular weight with non- zymes are extensively distributed and could be isolated volatilewater-soluble characteristics of colorless solid from indigenous sources including animals, plants, and crystals (6). hydratase is used to hydrolyze L-Asparaginase potential in acrylamide mitigation from foodstuff: a mini-review 499 specifically for the production of acryla- asparaginase, its sources as well as its role in reduction/ mide at commercial level available both in monomeric mitigation of acrylamide, potential carcinogenic agent, as well as polymeric forms. Polymeric acrylamide as from foods baked or fried at high temperature with have versatile application including low moisture content. the clarifying agent for drinking water; coagulant in wastewater treatment; applications in theconstruc- tion of dam foundations and tunnels as well as used L-Asparaginase and its History for the separation and purification of macromolecules in gel electrophoresis (7-9). The International Agency Normal body cells synthesized their own aspara- for Research on (IARC, 1994) has classified gine as a non-essential amino acid for cellular function acrylamide as ‘‘probably carcinogenic to humans’’ on with the help of asparagine synthetase and could also the basis of several studies. In 2002 Swedish National take this amino acid from blood circulation from ex- Food Administration (SNFA) was the first who re- trinsic sources so normal body cells grow autonomous corded acrylamide contents present in food products. of its requirement. On the other hand, thetumorcells The European Commission Scientific Committee on lack the ability to synthesize asparagine in vivo so they Food (10) reported the intrinsic toxic effects of acryla- totally depend on the availability of high amount of mide like neurotoxic, genotoxic to somatic as well as this amino acid for their survival as well as for uncon- to germ cells, carcinogenic effect and toxicity to re- trolled rapid proliferation (19). It was found first time productive organs. Recently anassociation between in 1922 that guinea pig serum has higher activity of different types of cancers risk viz ovarian, breast, en- L-asparaginase and it was determined later on that it dometrial and renal, and intake of acrylamide has been also possessed anti-neoplastic potential (20). Further, evaluated repeatedly (11, 12). in 1953 Kidd (21) used mice and rats as ananimal L-Asparaginase has attracted the attention of model to run the experimental trial for the evaluation food processing industries as a promising acrylamide of theanticancer potential of L-asparaginase isolated mitigating agent (13) as treatment of starchy food with from guinea pig serum. After thatin 1961 Broome (22) L-asparaginase decreases the synthesis of acrylamide investigated L-asparaginase was responsible in these- before frying at high temperature (14). When aspara- rum of guinea pig which significantly affects the pro- gine-rich foods with contents are heated at high liferation of lymphoblastic cells due to its antineoplas- temperature these foods undergo a process called the tic potential. Then in 1967 Oettgen and his colleague, Maillard reaction, this reaction is responsible for the first time determined the antineoplastic potential of induction of brown color, crust and toasted flavor in this enzyme in humans with leukemia. After that ap- baked or fried foods. L-asparaginase transformed the plication of L-asparaginase as ananti-acrylamide agent asparagine into aspartic acid and ammonium before was reported in food industries as L-asparaginase de- baking or frying the food and as a result, Maillard re- grade the asparagine present in foods especially in action takes place without the involvement of aspara- foods also having reducing sugars (23). So, during the gine, and therefore production of acrylamide in afinal baking procedure,L-asparaginase made asparagine un- food product is significantly reduced (15). Elimination available in Maillard reaction mostly in prod- of acrylamide completely from food products is im- ucts and (24, 25). possible due to the presence of minor pathways which are independent on asparagine (16). L-asparaginase as a food processing aid of starchy foods can efficiently Sources of L-Asparaginase trim down the level of acrylamide upto 88% to 90% and advantage on other mitigation strategy is degra- The requirements for thebulk amount of this en- dation of acrylamide would not affect the taste and zyme for industrial applications both for pharmaceuti- appearance of the final product/products (17, 18). So cal as well as for foods industries have been motivated in this review article, we have tried to described L- to find out new sources for L-asparaginase with high 500 N. Munir, M. Anjum Zia, S. Sharif, et al.

Table 1. Different sources of L-Asparginase production/isolation Bacterial Fungal Plants Pseudomonas aeruginosa (29) Aspergillus nieger (83) Pisum sativum (85) Bacillus subtilis (76) S. gulbargensis (34) Soyabean leaves (86) Coliform bacteria (77) Penicillium spp (32) Withania somnifera (87) E. coli (78) Aspergillus terreus MTCC (84) Soyabean seeds (88) Bacillus sp (79) Amaranthus polygonoides (89) Halophilic bacteria (80) Actinomycetes Algae Pectobacterium caratovorum (81) Actinomycete strain RAF 10 (90) Chlamydomonas (94) Proteus vulgaris (82) Streptomyces albidoflavus (91) Yeast Serratia marcescens (30) Streptomyces tendaeTKVL-333 (92) Pichia pastoris (95) Erwinia carotovora (1) Streptomyces ABR 2 (93) Rhodotorula spp. (96) Animals Streptomyces radiopugnans MS1 (81) Guinea pig serum (94) Candida utilis (97) Saccharomyces cerevisiae (98) specific activity and prolonged half-life. L-Asparagi- Acrylamide production follows various routes nases from various sources including plants (26, 27), along the Maillard reaction system in final products of bacteria (28-30),yeast and fungi (14, 31, 32) actino- food and asparagine is the major one which produced mycetes (33-35) algae and serum of some rodents (36, highest quantity of acrylamide during this reaction in 37) have been isolated and characterized for therapeu- result of (6) asparagine reaction with reducing sugars tic applications in the treatment of cancer as well as for primarily glucose and (Figure 2) along some food industries to reduce the production of acrylamide minor pathways (Figure 1) (45, 46). Maillard reaction during baking/frying process (29), further Table.1 de- is a reaction which is independent of any enzyme, the scribes the sources of L-Asparaginase which could be browning reaction occurred in foods in the result of used to reduce or mitigate the production of acryla- aspecific combination of proteins, carbohydrates, and mide in food industries. lipids on or frying to inducing desirable color, aroma, and flavor (47). Asparagine, a non-essential amino acid found in potatoes in high concentration Mechanism of acrylamide formation (93.6 mg/100 g) (46, 48), required carbohydrates for the production of acrylamide (49). Free Acrylamide is naturally absent from foods and is level in rye varieties to be the main determinant of not added extrinsically but during the frying process, acrylamide production (50) and in baked flours and it synthesized in different ratios. Research studies in- doughs (mainly rye and wheat) (51). The major limit- dicated that foods frying, baking and roasting at ahigh ing factors reported for acrylamide formation in po- temperature above 120°C could be a vital source of tatoes are the reducing sugars (52) and asparagine in acrylamide formation especially foods rich in carbohy- cereal products (53, 54). Molecular studies for tracking drate (reducing sugars) particularly (38, 39). the construction of acrylamide structural constituents In general, when foods are baked or processed during frying revealed that three Carbon atoms and at high temperature like potato products(24, 40) cof- one Nitrogen atom are derived from asparagine mol- fee (41), tea (42)bakery products (43)and others like ecule (45, 55). roasted almonds, , dry fruits (44) contained the In addition to asparagine and reducing sugars prominent concentration of acrylamide. Claus and his routes of acrylamide formation many minor acryla- co-workers (2010) calculated that the average acryla- mide production pathways recommended via. mide intake in adults ranges from 0.3 to 0.6 mg/kg and ammonia (Figure 1 & 2). Acrolein and ammonia body weight per day while ingestion of acrylamide in have a very important role in the formation of acryla- children and adolescents is high per body weight rang- mide in lipid-rich foods. It was well reported that deg- es 0.4–0.6 mg/kg (43). radation of triglycerides (lipids) at high temperature L-Asparaginase potential in acrylamide mitigation from foodstuff: a mini-review 501

Figure 1. Basic pathways for the formation of acrylamide in Figure 3. Concentration of acrylamide (μg kg-1) in various foods designed and modified from(6). foods/ food products produced on frying/baking (103, 106). Mitigating agents of acrylamide

Considerable efforts for the elimination/reduc- tion of acrylamide level in food products have been undertaken with the help of appropriate strategies. Reduction of acrylamide synthesis in food products could help to save the human being from food hazards as well as to generate awareness at household and in- dustrial levels about the food safety. Numerous strate- gies for the mitigation of acrylamide so far regarding acrylamide formation at diverse stages of food produc- tion have been undertaken(Table 2) (64). Acrylamide mitigation strategies should involve elimination of as- paragine alone, without affecting the other ingredients Figure 2. Formation of acrylamide from L-asparagine in the in the food; so that there would not be asignificant presence of α-hydroxycarbonyls/reducing sugars (Designed difference in the sensorial properties of the food prod- and modified from Stadler, Robert (15). ucts (65). At large scale many approaches have been made to decrease and eradicate acrylamide levels by produced acrolein and as aprecursor of the addition of filamentous fungi like A. oryzae (66) acrylamide in food products (56). Further, thebreak- antioxidants (67), compounds like allicin (68) and via down of amino acids with ammonia under low mois- applying different techniques based on genetic and ag- ture content at high thermal conditions could produce ronomic manipulations for the reduction of the levels acrylamide (57-59). of the most important precursors of acrylamide like Amino acids including cysteine, aspartic acid, and asparagine and sugars in produced plants (69, 70). The glutamine have also been investigated to play role in the amalgamation of some additives though may help in formation of asmall amount of acrylamide (Figure 1) the reduction of acrylamide, is to be expected to have (60, 61). However, it was reported that this route might aprofound impact on the flavor and quality of the food be unrelated to theproduction of acrylamide in foods products (71). Therefore, the use of L-asparaginase is (62). Generally, theintensity of color directly related to relatively a simpler and effective solution, which makes the level of acrylamide in food products and production it a potential contender for the reduction of acrylamide of acrylamide significantly increases towards the end of content in starchy fried food commodities in thefood the frying process (63). The concentration of acrylamide industry. L-Asparaginase pre-treatment of food mate- produced in various foods and food products has also rials before heat treatment is an appropriate solution been further summarized below (Fig. 3). suggested by several researchers (72, 73) as for the 502 N. Munir, M. Anjum Zia, S. Sharif, et al.

Table 2. Effect of L-Asparaginase on acrylamide synthesis Product Reduction of Acrylamide Preparation process/ References conc. (%) Treatment technique Potato product >99 Frying (45) Cracker products ≈ 70 Dough Based (99) French fries >90-99 Frying (40) Ginger biscuits, Semisweet biscuits, French 34-92 Dough Based (100) fries, Sliced potato chips and Crispbread Potato strips ≈ 80 frying/Immersion of Potato (101) Strips Potato strips 96 Frying (102) Sweet Dough Based (75) Gingerbread >97 Dough Based (71) Spanish rosquillas Upto 90 Dough Based (74) reduction of free asparagine and thereby to minimize the imminent risk of synthesis of acrylamide as sum- Table 3. Various strategies for Mitigation/Minimizing of Acrylamide content in processed food products marized in (Table 2). In addition, L-asparaginase pre- Strategies References treatment does not only leave the actual sensorial prop- 1. Establish Databases of foods for (103) erties of the final food products unaffected but also en- · Asparagine concentration hances the flavor by increasing the glutamic acid con- · Glucose concentration tent of the food. Further, L-asparaginase pretreatment 2. Investigation of the relationship between (103) reduced not only acrylamide but also the formation · Asparagine and acrylamide concentration in the processed and unprocessed foods of hydroxymethylfurfural, a genotoxic intermediate of 3. Limiting the concentration of acrylamide (104) Millard reaction (74, 75). L-Asparaginase is marketed precursors i.e Asparagine and glucose commercially as Acrylaway launched in 2007 by No- a. Asparagine can be decreased by vozymes, and as PreventASeL-asparaginase produced · Breeding for low asparagines biosynthesis · Suppressing genes that encode enzymes for from Aspergillusniger, developed by DSM. Further re- asparagines synthesis search aimed at how to reducethe acrylamide contents · Selecting from available cultivars contain- in food products should proceed following the differ- ing low conc. of asparagine ent strategies suggested (Table 3). b. Asparagine modification · Acetylation of Asparagine to N-acetylas- paragine prevent acrylamide formation fromN-glycoside intermediates Conclusion 4. Destruction and modification of acrylamide (105) to make less toxic or harmless Acrylamide contents in foodstuff with well report- a. Hydrolysis by · Acid and/ enzymes to degrade acrylamide ed toxic effects including carcinogenicity, genotoxicity, formed in processed foods reproductive &neurotoxicity arelargely resulted from b. Polymerization of monomeric acrylamide by the reaction of R-amino group of the free amino acid · Radiations, UV light asparagine with a carbonyl group(s) of reducing sugars · Free radical induced including one-electron oxidation intermediates of phenolic com- such as glucose on applying heat as amajor pathway pounds and flavonoids (e.g., catechin, chlo- along with some minor pathways. Strategies to reduce rogenic acid, tyrosine) Maillard browning the concentration of L-asparagine and/or glucose con- products, tryptophan, and fatty acids tent in unheated foods are expected to result in the c. Binding of acrylamide with SH-containing reduction of acrylamide production in final food prod- amino acids, esters, peptides, and proteins d. Decreasing synthesis by lowering pH using ucts. 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